Testosterone replacement therapy (TRT) produces documented side effects that vary in clinical importance. Some, like erythrocytosis and fertility suppression, are predictable pharmacological consequences of supraphysiologic testosterone exposure or exogenous androgen administration. Others, like cardiovascular risk, were contested for years and clarified by a major trial in 2023. Understanding which side effects are well-established versus theoretical helps patients and clinicians make informed decisions.

Erythrocytosis (High Red Blood Cell Count)

The most consistently documented side effect of TRT is erythrocytosis: an increase in red blood cell production driven by testosterone’s stimulation of erythropoietin. This is a dose-dependent effect, higher testosterone levels produce more erythrocytosis.

Clinically elevated hematocrit (above 52-54%) increases blood viscosity and, at sustained high levels, raises the risk of thrombotic events including deep vein thrombosis and stroke. The Testosterone Trials and observational data consistently find erythrocytosis rates of 5-10% in men on TRT, with higher rates in those using injectable testosterone (which produces higher peak levels) compared to topical gels.

Monitoring hematocrit every three to six months during TRT is standard practice. If hematocrit exceeds 54%, dose reduction or temporary cessation is indicated. Some clinicians use therapeutic phlebotomy (blood donation) to manage erythrocytosis in patients who cannot tolerate dose reduction.

Testicular Atrophy and Suppression of Natural Production

Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis. The hypothalamus detects elevated testosterone and reduces GnRH output, which causes the pituitary to reduce LH and FSH. Without LH stimulation, the testes stop producing testosterone and partially atrophy in size. This effect is reversible but recovery time after TRT cessation varies widely, from weeks to over a year.

This is not a harm in the traditional sense for men who intend to remain on TRT indefinitely. It becomes a significant concern for men who want to preserve the option to discontinue treatment and recover natural testosterone production, and for men who want to preserve fertility.

Fertility Suppression

TRT reliably suppresses sperm production. FSH is required for spermatogenesis; when TRT suppresses FSH, sperm production falls dramatically and sometimes to zero. This makes TRT essentially a form of male contraception, though it is not reliable enough to be used as such.

Sperm production typically recovers after TRT is discontinued, but recovery time is unpredictable and not guaranteed. Men who want to have children should discuss alternatives to TRT, including clomiphene citrate, HCG, or no treatment, with a urologist or reproductive endocrinologist before starting TRT. A full discussion of this tradeoff is in Testosterone and Fertility: What TRT Does to Sperm.

Skin and Hair Effects

Testosterone is converted to dihydrotestosterone (DHT) by 5-alpha reductase in the skin and other tissues. Elevated DHT can accelerate male pattern hair loss in men genetically predisposed to it. TRT does not cause hair loss in men without the genetic predisposition, but it can accelerate the process in men who would have experienced it anyway.

Acne is a common side effect, particularly on the back and shoulders. It is most common with injectable testosterone during peak levels in the days immediately after injection. Topical gels produce more stable levels and less acne in many patients.

Cardiovascular Effects: What the TRAVERSE Trial Showed

For years, TRT’s cardiovascular safety was uncertain. A 2010 trial published in the New England Journal of Medicine raised concerns about increased cardiovascular events in older men on TRT. This was followed by conflicting observational data and regulatory scrutiny.

The TRAVERSE trial, published in 2023, provided the most definitive answer to date. This randomized controlled trial enrolled 5,246 men with hypogonadism and cardiovascular disease or high cardiovascular risk and followed them for over four years on testosterone gel or placebo. The primary cardiovascular outcomes, heart attack, stroke, and cardiovascular death, were not statistically different between groups.

The TRAVERSE trial resolved the major cardiovascular safety question, finding that TRT in hypogonadal men with cardiovascular risk did not increase major cardiovascular events compared to placebo. However, the trial also found a higher rate of atrial fibrillation, pulmonary embolism, and acute kidney injury in the testosterone group. These were secondary findings but warrant monitoring.

Prostate Effects

TRT is contraindicated in men with known prostate cancer. It raises PSA (prostate-specific antigen) in most men by 0.3-1.0 ng/mL, which can complicate screening. Baseline PSA measurement before starting TRT and regular monitoring afterward are standard.

The long-standing concern that TRT causes prostate cancer is not well supported by the current evidence. The saturation model of prostate androgen sensitivity, which proposes that prostate tissue is maximally stimulated at low testosterone levels and does not respond further to higher levels, is now the dominant framework, and prospective data has not confirmed TRT as a cause of prostate cancer.

What Gets Regular Monitoring on TRT

  • Hematocrit and hemoglobin: every 3-6 months
  • PSA: at baseline, 3-6 months, then annually
  • Testosterone levels: to confirm therapeutic range
  • Lipid panel: annually
  • Bone density: if starting TRT due to osteoporosis risk

For more on how TRT is delivered and what the delivery method affects, see Testosterone Injections vs. Gel: Which Delivery Method Is Better?.